Process for the production of amorphous atorvastatin calcium

ABSTRACT

A process for the preparation of amorphous atorvastatin calcium and hydrates thereof which comprises: (a) dissolving crystalline atorvastatin calcium in a non-hydroxylic solvent; (b) adding a non-polar hydrocarbon anti-solvent or adding the dissolved atorvastatin to the non-polar anti-solvent to precipitate out atorvastatin calcium; and (c) removing the solvent by filtration to afford amorphous atorvastatin calcium.

FIELD OF THE INVENTION

[0001] The present invention relates to a process for the production ofamorphous atorvastatin calcium.

BACKGROUND OF THE INVENTION

[0002] Atorvastatin is chemically [R-(R*,R*)]-2-(4-fluoro-phenyl)-βdihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-1Hpyrrole-1-heptanoic acid. Atorvastatin calcium, a synthetic HMG-CoAreductase inhibitor, is used for the treatment of hyperlipidemia andhypercholesterolemia, both of which are risk factors forarteriosclerosis and coronary heart disease. Open dihydroxy carboxylicacid, lactone and various salt forms of atorvastatin have beensynthesized.

[0003] U.S. Pat. No. 5,273,995, describes that R-form of the ring openedacid form has surprising inhibition of the biosynthesis of cholesterol.Atorvastatin in its calcium salt form, i.e.[R-(R*,R*)]-2-(4-fluoro-phenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbomyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) having Formula1:

[0004] is more suited to formulations and has been recommended as adrug.

[0005] U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482;5,149,837; 5,248,793; 5,280,126; 5,342,952, which are hereinincorporated by reference, describe various processes and keyintermediates for preparing atorvastatin.

[0006] Atorvastatin calcium produced by the processes described in theabove mentioned United States patents does not give amorphousatorvastatin consistently but gives a mixture of its crystalline andamorphous forms, which has unsuitable filtration and dryingcharacteristics and are not suitable for large-scale production.

[0007] PCT application, WO 97/03959, discloses novel crystalline formsof atorvastatin calcium designated as Form I, Form II, and Form IV andmethod for their preparation which provide more favourable filtrationand drying characteristics.

[0008] PCT application WO 97/03960 describes a procedure for convertingthe crystalline form of atorvastatin to the amorphous form. Processdisclosed therein comprises dissolving crystalline form-I atorvastatinin a non-hydroxylic solvent like tetrahydrofuran or mixtures oftetrahydrofuran and toluene. The process involves complete removal ofthe solvent under high temperature (about 90° C.) and high vacuum (about5 mm) using capital intensive equipment. Exposure of the material tohigh temperature for several days leads to degradation of the product.This makes the process very inconvenient to operate at a large scale.Slow removal of solvents at a manufacturing scale renders this processas inefficient cost-wise and less productive.

SUMMARY OF THE INVENTION

[0009] It is an objective of the present invention to provide anefficient process for the production of amorphous atorvastatin, whicheliminates the problems of prior art and is convenient to operate on acommercial scale.

[0010] Accordingly, the present invention provides a process for thepreparation of atorvastatin calcium in an amorphous form which comprisesdissolving crystalline atorvastatin in a non-hydroxylic solvent, addinga suitable non-polar hydro-carbon solvent and recovering atorvastatinfrom a solution thereof, by solvent precipitation, isolating and dryingthe product.

[0011] Generally, the product can be isolated by any standard methodknown in the art such as by filtration, centrifugation or decantation.Typically, this product is isolated by filtration when any of thesolvents within the scope of the process are used.

[0012] Major advantages of the present invention compared to the priorart processes are:

[0013] i. elimination of the need to remove solvent by dryingtechniques.

[0014] ii. less time consuming with improved filtration.

[0015] iii. easy to operate on large-scale.

[0016] iv. reproducibly produces amorphous product having allowablelevels of residual solvents.

[0017] The present invention thus provides a novel process for thepreparation of amorphous atorvastatin calcium and hydrates thereof whichcomprises:

[0018] (a) dissolving crystalline atorvastatin calcium in anon-hydroxylic solvent;

[0019] (b) adding a non-polar hydrocarbon anti-solvent to precipitateout the material; and

[0020] (c) removing the solvent by filtration to afford amorphousatorvastatin calcium

[0021] The non-hydroxylic solvent is selected from a group of solvents,which have the ability to dissolve crystalline atorvastatin and includestetrahydrofuran. Suitable non-polar hydrocarbon solvents are selectedfrom a group consisting of: n-hexane, n-heptane, cyclohexane, hexanefraction, heptane fraction or the like. In a preferred embodiment ofthis invention, the non-hydroxylic solvent is tetrahydrofuran andanti-solvent is n-hexane, cyclohexane or n-heptane.

[0022] Generally, crystalline atorvastatin calcium is dissolved in anon-hydroxylic solvent, e.g. tetrahydrofuran, at a concentration ofabout 15% w/v to about 40% w/v, preferably at a concentration of about25% w/v to about 15% w/v at ambient temperature and a non-polarhydrocarbon, preferably n-hexane, cyclohexane or n-heptane, is added at0° C. to 50° C., preferably at 20° C. to 25° C. The product is recoveredby filtration at ambient temperature. Filtration, which is fast andsmooth, is carried out using nutsche filtration or centrifugefiltration. Preferably, nutsche filtration is used on large scalepreparation. Filtered material, a semi-dry powder, is further dried toremove surface solvents in a vacuum tray drier, tray drier, fluid beddrier or a rotary vacuum drier to afford amorphous material. Preferably,material is dried in a vacuum tray drier at about 20° C. to about 80° C.for 6 hours to 24 hours. Most preferably, drying is carried out at about50° C. to about 60° C. for 12 hours.

[0023] Quantity of antisolvent varies from 5 times to 50 times the inputof crystalline atorvastatin calcium depending upon its solution innon-hydroxylic solvent. Preferably, the quantity of antisolvent used isabout 20 times to about 40 times the input of crystalline atorvastatincalcium to make overall concentration of about 5% w/v to about 2.5 w/v%.

[0024] Amorphous atorvastatin calcium prepared according to the processof the present invention may be characterized by its x-ray powderdiffration pattern (FIG. 2) as shown in the accompanied drawings. X-raypowder diffration patterns (FIG. 2) show no peaks which arecharacteristic of a crystalline atorvastatin calcium (FIG. 1 of theaccompanied drawings) thus demonstrating the amorphous nature of theproduct.

BRIEF DESCRIPTION OF THE FIGURES

[0025]FIG. 1 is the diffractogram of crystalline atorvastatin calcium.The horizontal axis represents 2θ and the vertical axis corresponds topeak intensity.

[0026]FIG. 2 is diffractogram of amorphous atorvastatin calcium. Thehorizontal axis represents 2θ and the vertical axis corresponds to peakintensity.

[0027] The present invention is illustrated by the following examples,which are not intended to limit the effective scope of the claims.

DETAILED DESCRIPTION OF THE INVENTION Example 1

[0028] [R-(R*,R*)-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-1H-pyrrole-1-heptanoicAcid Hemicalcium Salt (Amorphous Atorvasatin Calcium).

[0029] Method A

[0030] Crystalline atorvastatin calcium (10 kg) was dissolved intetrahydrofuran (30 lt) under stirring at ambient temperature. Clearsolution so obtained was added slowly to cyclohexane (350 lt) undernitrogen atmosphere. It was vigorously stirred maintaining temperatureat 20-25° C. The precipitated product was centrifuged and dried undervacuum at about 60° C. for 12 hours. Atorvastatin (9.5 kg) in anamorphous form was obtained having residual solvent levels of 0.01% w/wtetrahydrofuran and 0.6% w/w cyclohexane. X-ray powder diffractionpattern (FIG. 2 as shown in the accompanied drawings) demonstrate theamorphous nature of the product.

[0031] Method B

[0032] Crystalline atorvastatin calcium (10 kg) was dissolved intetrahydrofuran (30 lt) under stirring at ambient temperature. To aclear solution of atorvastatin, cyclohexane (350 lt) was added undervigorous stirring at 20 to 25° C. The precipitated mass was furtherstirred for 30 minutes and filtered in a centrifuge. The product wasdried under vacuum at about 60° C. for 12 hours. Atorvastatin (9.6 kg)in an amorphous form was obtained having residual solvent levels of0.01% w/w for tetrahydrofuran and 0.7% w/w for cyclohexane. X-ray powderdiffraction pattern demonstrates the amorphous nature of the product.

Example 2

[0033] [R-(R*,R*)-2-(4-fluorophenyl)β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-1H-pyrrole-1-heptanoicAcid Hemicalcium Salt (Amorphous Atorvasatin Calcium)

[0034] The process of Example 1 was repeated with crystallineatorvastatin calcium (10 kg) dissolved in tetrahydrofuran (30 lt) andusing n-hexane instead of cyclohexane to give amorphous atorvastatin(9.5 kg.). X-ray crystallography confirmed the amorphous nature of theproduct.

Example 3

[0035] [R-(R*,R*)]-2-4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl)-1H-pyrrole-1-heptanoicAcid Hemicalcium Salt (Amorphous Atorvasatin Calcium)

[0036] The process of Example 1 was repeated with crystallineatorvastatin calcium (10 kg) dissolved in tetrahydrofuran (30 lt) andusing n-heptane instead of cylcohexane to give amorphous atorvastatin(9.6 kg). X-ray crystallography examination confirmed the amorphousnature of the product.

[0037] While the present invention has been described in terms of itsspecific embodiments, certain modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of the present invention.

We claim:
 1. A process for the preparation of amorphous atorvastatincalcium and hydrates thereof which comprises: (a) dissolving crystallineatorvastatin calcium in a non-hydroxylic solvent; (b) adding a non-polarhydrocarbon anti-solvent or adding the dissolved atorvastatin to thenon-polar anti-solvent to precipitate out atorvastatin calcium; and (c)removing the solvent by filtration to afford amorphous atorvastatincalcium.
 2. The process of claim 1, wherein the non-hydroxylic solventis tetrahydrofuran and anti-solvent is chosen from a group of non-polarhydrocarbon solvents comprising n-hexane, cyclohexane or n-heptane. 3.The process of claim 1, wherein the non-hydroxylic solvent istetrahydrofuran and anti-solvent is n-hexane.
 4. The process of claim 1,wherein the non-hydroxylic solvent is tetrahydrofuran and anti-solventis cylcohexane.
 5. The process of claim 1, wherein the non-hydroxylicsolvent is tetrahydrofuran and anti-solvent is n-heptane.
 6. The processof claim 1, wherein said amorphous atorvastatin calcium is isolated byfiltration.